DESCRIPTION: The research proposed investigates the expression and functional role of a chemokine homologue encoded by murine cytomegalovirus (MCMV). Dr. MacDonald has noted that the deduced sequence of a MCMV open reading frame is highly homologous to members of the CC (Beta) class of chemokines. This is the first example of a virus possibly producing a cytokine and its receptor. Beta chemokines are small mammalian molecules which are chemotactic for leukocytes, including monocyte/macrophages, cells that play a prominent role in CMV infection. Utilizing in vitro chemotaxis, calcium mobilization and binding assays, Dr. MacDonald will determine whether this chemokine homologue, designated MCK-1, exhibits agonist or antagonist activity for endogenous chemokine receptors present on primary murine macrophages, as well as macrophage cell lines. The expression of RNA encoding MCK-1 will be characterized by molecular methods in infected tissue culture cells, as well as in tissues from infected mice. The role of MCK-1 in MCMV pathogenesis will be investigated by administration of MCK-1 neutralizing antibodies and by the generation of a recombinant MCMV lacking functional MCK-1. Effects on tissue viral titers, LD50 and the inflammatory response will be determined. These studies will provide insight into the role of chemokines in HCMV pathogenesis, leading to possible therapeutic and/or preventative interventions for this human pathogen.